EP2366408B1 - Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation - Google Patents

Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation Download PDF

Info

Publication number
EP2366408B1
EP2366408B1 EP10155005A EP10155005A EP2366408B1 EP 2366408 B1 EP2366408 B1 EP 2366408B1 EP 10155005 A EP10155005 A EP 10155005A EP 10155005 A EP10155005 A EP 10155005A EP 2366408 B1 EP2366408 B1 EP 2366408B1
Authority
EP
European Patent Office
Prior art keywords
sodium
pharmaceutical composition
pharmaceutically acceptable
polyoxyethylene
potassium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP10155005A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2366408A1 (en
Inventor
Jaume Ruiz I Pol
Francisca Izquierdo Torres
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratorios Salvat SA
Original Assignee
Laboratorios Salvat SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios Salvat SA filed Critical Laboratorios Salvat SA
Priority to EP10155005A priority Critical patent/EP2366408B1/en
Priority to DK10155005.1T priority patent/DK2366408T3/da
Priority to ES10155005T priority patent/ES2391721T3/es
Priority to PL10155005T priority patent/PL2366408T3/pl
Priority to US12/730,681 priority patent/US8932610B2/en
Priority to AU2011223095A priority patent/AU2011223095B2/en
Priority to CN201180009966.6A priority patent/CN102811741B/zh
Priority to RU2012141641/15A priority patent/RU2549465C2/ru
Priority to KR1020127025195A priority patent/KR101777157B1/ko
Priority to CA2790652A priority patent/CA2790652C/en
Priority to JP2012555383A priority patent/JP5744922B2/ja
Priority to PCT/EP2011/052939 priority patent/WO2011107436A2/en
Priority to MX2012010009A priority patent/MX2012010009A/es
Priority to BR112012021638-4A priority patent/BR112012021638B1/pt
Priority to ARP110100633A priority patent/AR080368A1/es
Publication of EP2366408A1 publication Critical patent/EP2366408A1/en
Priority to HK12102610.2A priority patent/HK1162145A1/xx
Application granted granted Critical
Publication of EP2366408B1 publication Critical patent/EP2366408B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to compositions of Fluocinolone Acetonide as anti-inflammatory active pharmaceutical ingredient, for use in the treatment of otic inflammation, optionally accompanied by bacterial infection.
  • Fluocinolone Acetonide is an anti-inflammatory corticosteroid successfully used for topical treatment of otic inflammation. It is known in combination with an antibacterial and an antiseptic for treatment of external or middle ear infections (cf. e.g. US 20090111780 A1 ).
  • Fluocinolone Acetonide (a 6,9-difluoro-16,17-acetonide corticosteroid) is classified as high to medium potency anti-inflammatory agent depending on the concentration and the vehicle used.
  • the 9-F group increases glucocorticoid activity and prevents metabolic oxidation of the 11-OH group (cf. e.g. T.L. Lemke and D.A. Williams, "Foye's Principles of Medicinal Chemistry", Wolters Kluwer 2007, 6th ed., p. 902 ).
  • Fluocinolone Acetonide is virtually insoluble in water. It is actually more insoluble than other corticosteroids (e.g. Dexamethasone or Hydrocortisone) that are also used for similar purposes.
  • the acetonide (ketal) moiety at the 16,17-position of fluocinolone provides potency as topical anti-inflammatory agent as it enhances lipophilicity (ibid, p. 895), but consequently reduces solubility.
  • otic drops containing Fluocinolone Acetonide are organic solutions (e.g. otic oil drops commercialized by Hill Dermaceuticals) or aqueous-organic suspensions (e.g. the aqueous suspension preparations described in EP 1312356 A1 ).
  • Otic drops containing Fluocinolone Acetonide and Ciprofloxacin are on the market in the form of aqueous-organic composition containing preservatives and less than 75% of water (e.g. otic drops commercialized by Salvat in Spain for treatment of external otitis).
  • disorders that entail otic inflammation are eczematoid external otitis, keloids, granular myringitis, bullous myringitis or sudden deafness.
  • Examples of disorders that entail otic inflammation accompanied by bacterial infection are diffuse external otitis (swimmers's ear), localized external otitis (forunculosis), traumatic tympanic membrane perforations, herpes zoster oticus (Ramsay Hunt syndrome), otitis media with effusión (OME, also called serous or secretory otitis media (SOM) or glue ear), otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes (AOMT), acute otitis media (AOM) or chronic suppurative otitis media (CSOM).
  • diffuse external otitis swimmers's ear
  • localized external otitis forunculosis
  • traumatic tympanic membrane perforations herpes zoster oticus
  • OME otitis media with effusión
  • SOM serous
  • US 2010/036000 A1 discloses the treatment of several otic diseases with antimicrobials and possibly additional therapeutic agents in sterile preparations to be administered locally
  • GB 1 411 432 A discloses preparations comprising urea and surfactants (where the surfactants also act as viscosifiers), as a vehicle for e.g. fluocinolone acetonide (FA) in dermatologic compositions.
  • FA fluocinolone acetonide
  • the present invention provides a pharmaceutical otic sterile preservative-free composition in the form of a clear aqueous solution of Fluocinolone Acetonide that comprises more than 90% water (all percentages are w/v), and which is suitable for administration as drops from a single-dose container (obviously, although not specially preferred, administration from a multi-dose container would also be possible).
  • Dropping an otic liquid pharmaceutical composition from single-dose containers has many advantages. For example, it permits the administration of a precise dose of the composition. Another advantage is that, since a new container is open each time, the administered composition is always sterile, thus avoiding the possibility of contamination by microorganisms or by body secretions. Besides the advantage of greater hygiene, the single-dose container is also more pleasant to use and manipulate than multi-dose containers.
  • an otic composition must fulfill several requirements, which appeared to be difficult in the case of a highly insoluble active pharmaceutical ingredient, such as Fluocinolone Acetonide. If, as customary, sterilization is to be done by filtration through a 0.22 ⁇ m filter, the composition must be a clear solution, i.e. substantially free from particles in suspension. Besides, it is highly desirable that the solution is free from preservatives, such as methylparaben and propylparaben.
  • Inventors have found that it is appropriate to use a total amount of 0.5-4.0% of one or more nonionic surfactants with a hydrophilic-lipophilic balance (HLB) value between 14 and 18 to obtain a pharmaceutical otic sterile preservative-free composition in the form of a clear aqueous solution (i.e. substantially free from particles in suspension) of 0.01-0.10% of Fluocinolone Acetonide.
  • a total amount of 0.5-4.0% of one or more tonicity adjusting agents is appropriate for adjusting tonicity
  • a total amount of 0.05-1.00% of one or more viscosity increasing agents is appropriate for adjusting viscosity.
  • the composition can optionally comprise an amount of one or more pH adjusting agents to adjust pH between 4.0 and 5.0.
  • These excipients in the mentioned amounts, also provide a pharmaceutical otic sterile preservative-free composition in the form of a clear aqueous solution in the case that Fluocinolone Acetonide is accompanied by 0.1-0.8% of Ciprofloxacin or a pharmaceutically acceptable salt thereof, this composition being useful when otic inflammation is accompanied by bacterial infection.
  • the pharmaceutical composition of the present invention shows a number of advantages. It is a clear aqueous solution substantially free from solid particles in suspension that can be sterilized by filtration without loss of active ingredient, which entails good dose reproducibility. It shows also good stability. This allows having a sterile preservative-free composition that can be contained in disposable single-dose containers for topical use in drop form. Also, lack of preservatives and of non-aqueous solvents avoids the possible adverse effects that might cause these compounds.
  • nonionic surfactants with a HLB value between 14 and 18 include, but are not limited to sorbitan polyoxyethylene fatty acid derivatives; polyoxyethylene hydrogenated castor oil derivatives; polyoxyethylene fatty acid derivatives, polyoxyethylene-polyoxypropylene co-polymers and block-co-polymers..
  • the pharmaceutically acceptable examples of nonionic surfactants with a HLB value between 14 and 18 are selected from the group consisting of sorbitan polyoxyethylene fatty acid derivatives such as Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); polyoxyethylene hydrogenated castor oil derivatives such as polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene glycol (60) hydrogenated castor oil and polyoxyethylene glycol (40) hydrogenated castor oil; polyoxyethylene fatty acid derivatives such as polyoxyethylene (20) stearate, polyoxyethylene (32) distearate, polyoxyethylene (20) oleate, polyoxyethylene (32) oleate and polyoxyethylene (32) dioleate; fatty alcohol ethoxylates such as
  • the pharmaceutically acceptable tonicity adjuster agents are selected from the group consisting of dextrose, glycerin, sorbitol, mannitol, xylitol, polyethylene glycol, propylene glycol, dextran or electrolytes such as potassium chloride, sodium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, calcium carbonate and sodium lactate.
  • the tonicity adjuster agent is glycerin.
  • the pharmaceutically acceptable viscosity increasing agents are selected from the group consisting of polyvinylpirrolidone, such as Povidone K 25, Povidone K 30 and Povidone K 90F; polyvinyl alcohol, xanthan gum, guar gum, welan gum, tragacanth gum, ceratonia gum, agar, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyethylene glycol, glycerin, carrageenan , sodium alginate, potassium alginate, propylene glycol alginate, sodium hyaluronate, carbomers and maltodextrin.
  • polyvinylpirrolidone such as Povidone K 25, Povidone K 30 and Povidone K 90F
  • the viscosity increasing agent is a polyvinylpirrolidone selected from Povidone K 25, Povidone K 30 and Povidone K 90F. In a particularly preferred embodiment the viscosity increasing agent is Povidone K 90F.
  • pH adjusting agents can be added, as solids or as aqueous solutions.
  • Pharmaceutically acceptable examples of pH adjusting agents include, but are not limited to, citric acid and salts thereof; tartaric acid and salts thereof, phosphoric acid and salts thereof, carbonic acid and salts thereof, lactic acid and salts thereof, acetic acid and salts thereof, sulphuric acid and salts thereof, boric acid and salts thereof, maleic acid and salts thereof, succinic acid and salts thereof; hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine or mixtures thereof.
  • the pharmaceutically acceptable pH adjusting agents are selected from the group consisting of citric acid and salts thereof, such as sodium citrate, potassium citrate, calcium citrate and lithium citrate; tartaric acid and salts thereof, such as sodium tartrate, potassium tartrate, calcium tartrate and lithium tartrate; phosphoric acid and salts thereof, such as sodium dihydrogenphosphate and sodium monohydrogenphosphate, lithium phosphate, potassium phosphate and calcium phosphate; carbonic acid and salts thereof, such as sodium carbonate and sodium hydrogencarbonate; lactic acid and salts thereof, such as sodium lactate, potassium lactate and calcium lactate; acetic acid and salts thereof, such as sodium acetate, potassium acetate and calcium acetate; sulphuric acid and salts thereof, such as sodium sulphate and potassium sulphate; boric acid and salts thereof, such as sodium borate; maleic acid and salts thereof, such as lithium maleate, sodium maleate, potassium maleate and calcium maleate; succinic acid and salts
  • the pharmaceutical composition comprises the following ingredients: 0.02-0.03% of Fluocinolone Acetonide, optionally accompanied by 0.2-0.4% of Ciprofloxacin or a pharmaceutically acceptable salt thereof; 2-3% of Polysorbate 80; 2-3% of glycerin; 0.1-0.3% of Povidone K 90F; optionally, an amount of one or more pharmaceutically acceptable pH adjusting agent q.s. to adjust pH 4.0-5.0; and water
  • the composition consist exclusively of the above mentioned ingredients.
  • the pharmaceutical composition has the following composition: 0.025% of Fluocinolone Acetonide; 2.5% of Polysorbate 80; 2.4% of glycerin; 0.2% of Povidone K 90F; sodium lactate q.s. to adjust pH 4.0-5.0 and water q.s. 100%.
  • the pharmaceutical composition has the following composition: 0.025% of Fluocinolone Acetonide, 0.349% of ciprofloxacin HCl; 2.5% of Polysorbate 80; 2.4% of glycerin; 0.2% of Povidone K 90F; and water q.s. 100%.
  • the pharmaceutical composition is sterilized and contained in disposable single-dose containers for topical use in drop form.
  • Another aspect of the invention relates to a method for the prevention and/or treatment of an individual suffering from otic inflammation, optionally accompanied by bacterial infection, comprising the topical administration to the individual of a therapeutically effective amount of the pharmaceutical composition as described above.
  • the otic inflammation is eczematoid external otitis, keloids, granular myringitis, bullous myringitis or sudden deafness.
  • the otic inflammation accompanied by bacterial infection is diffuse external otitis (swimmers's ear), localized external otitis (forunculosis), traumatic tympanic membrane perforations, herpes zoster oticus (Ramsay Hunt syndrome), otitis media with effusión (OME, also called glue ear), otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes (AOMT), acute otitis media (AOM) or chronic suppurative otitis media (CSOM).
  • Another aspect of the invention refers to a pharmaceutical composition as described above for its use as a medicament.
  • its use is for the prevention and/or treatment of otic inflammation, optionally accompanied by bacterial infection.
  • Another aspect of the invention is the use of the pharmaceutical composition as described above for the preparation of a medicament for the prevention and/or treatment of otic inflammation, optionally accompanied by bacterial infection.
  • Another aspect of the invention is a method for the prevention and/or treatment of an individual suffering from otic inflammation, optionally accompanied by bacterial infection, comprising the topical administration to the individual of a therapeutically effective amount of a pharmaceutical composition described above.
  • the otic inflammation is eczematoid external otitis, keloids, granular myringitis, bullous myringitis or sudden deafness.
  • the otic inflammation accompanied by bacterial infection is diffuse external otitis, localized external otitis, traumatic tympanic membrane perforations, herpes zoster oticus, otitis media with effusión, otorrhea through tympanostomy tubes, acute otitis media with tympanostomy tubes, acute otitis media or chronic suppurative otitis media.
  • Example 1 Aqueous solution comprising Fluocinolone
  • Example 2 Aqueous solution comprising Fluocinolone + Ciprofloxacin
  • Example 3 Aqueous solution comprising Fluocinolone
  • Example 4 Aqueous solution comprising Fluocinolone + Ciprofloxacin
  • Example 5 Aqueous solution comprising Fluocinolone
  • Concentrations of active ingredient in two batches of a pharmaceutical composition comprising Fluocinolone Acetonide and Ciprofloxacin were measured before and after filtration to confirm the absence of active particles in suspension that could be retained in the 0.22 ⁇ m filter leading to a loss of active ingredient.
  • Dynamic light scattering determinations of a pharmaceutical composition comprising Fluocinolone Acetonide and ciprofloxacin were carried out before and after filtration to confirm the absence of active particles in suspension that could be retained in the 0.22 ⁇ m filter leading to a loss of active ingredient.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP10155005A 2010-03-01 2010-03-01 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation Active EP2366408B1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
EP10155005A EP2366408B1 (en) 2010-03-01 2010-03-01 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
DK10155005.1T DK2366408T3 (da) 2010-03-01 2010-03-01 Vandige, klare opløsninger af fluocinolonacetonid til behandling af inflammation i øret
ES10155005T ES2391721T3 (es) 2010-03-01 2010-03-01 Disoluciones acuosas transparentes de acetónido de fluocinolona para el tratamiento de la infamación de oído
PL10155005T PL2366408T3 (pl) 2010-03-01 2010-03-01 Klarowne roztwory wodne acetonidu fluocinolonu do leczenia zapalenia uszu
US12/730,681 US8932610B2 (en) 2010-03-01 2010-03-24 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
CA2790652A CA2790652C (en) 2010-03-01 2011-02-28 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
RU2012141641/15A RU2549465C2 (ru) 2010-03-01 2011-02-28 Водные прозрачные растворы флуоцинолона ацетонида для лечения ушного воспаления
KR1020127025195A KR101777157B1 (ko) 2010-03-01 2011-02-28 귀 염증 치료용 플루오시놀론 아세토나이드의 맑은 수용액
AU2011223095A AU2011223095B2 (en) 2010-03-01 2011-02-28 Aqueous clear solutions of Fluocinolone Acetonide for treatment of otic inflammation
JP2012555383A JP5744922B2 (ja) 2010-03-01 2011-02-28 耳の炎症の治療を目的とするフルオシノロンアセトニドの透明な水性溶液
PCT/EP2011/052939 WO2011107436A2 (en) 2010-03-01 2011-02-28 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
MX2012010009A MX2012010009A (es) 2010-03-01 2011-02-28 Disoluciones acuosas transparentes de acetonido de fluocinolona para el tratamiento de la inflamacion de oido.
BR112012021638-4A BR112012021638B1 (pt) 2010-03-01 2011-02-28 composição livre de conservante estéril ótica farmacêutica na forma de uma solução aquosa clara
CN201180009966.6A CN102811741B (zh) 2010-03-01 2011-02-28 用于治疗耳部炎症的氟轻松澄清水溶液
ARP110100633A AR080368A1 (es) 2010-03-01 2011-03-01 Disoluciones acuosas transparentes de acetonido de fluocinolona para el tratamiento de la inflamacion de oido
HK12102610.2A HK1162145A1 (en) 2010-03-01 2012-03-14 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP10155005A EP2366408B1 (en) 2010-03-01 2010-03-01 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation

Publications (2)

Publication Number Publication Date
EP2366408A1 EP2366408A1 (en) 2011-09-21
EP2366408B1 true EP2366408B1 (en) 2012-07-18

Family

ID=42668238

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10155005A Active EP2366408B1 (en) 2010-03-01 2010-03-01 Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation

Country Status (16)

Country Link
US (1) US8932610B2 (ru)
EP (1) EP2366408B1 (ru)
JP (1) JP5744922B2 (ru)
KR (1) KR101777157B1 (ru)
CN (1) CN102811741B (ru)
AR (1) AR080368A1 (ru)
AU (1) AU2011223095B2 (ru)
BR (1) BR112012021638B1 (ru)
CA (1) CA2790652C (ru)
DK (1) DK2366408T3 (ru)
ES (1) ES2391721T3 (ru)
HK (1) HK1162145A1 (ru)
MX (1) MX2012010009A (ru)
PL (1) PL2366408T3 (ru)
RU (1) RU2549465C2 (ru)
WO (1) WO2011107436A2 (ru)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2604413C1 (ru) * 2015-06-17 2016-12-10 Марина Николаевна Вольгова Способ лечения хронического аллергического наружного отита
WO2016208742A1 (ja) * 2015-06-25 2016-12-29 参天製薬株式会社 注射剤
JP6255134B1 (ja) * 2016-11-02 2017-12-27 ヴェローチェ・バイオファーマ・エルエルシー 耳炎の治療のための組成物および方法
KR102094228B1 (ko) 2017-12-18 2020-03-27 경희대학교 산학협력단 운카리아 린초필라 추출물을 유효성분으로 포함하는 난청의 예방 또는 치료용 조성물
KR102075694B1 (ko) 2017-12-18 2020-02-10 경희대학교 산학협력단 시지지움 큐미니 추출물을 유효성분으로 포함하는 난청의 예방 또는 치료용 조성물
KR102007096B1 (ko) 2017-12-18 2019-08-02 경희대학교 산학협력단 비스쿰 오발리포리움 추출물을 유효성분으로 포함하는 난청의 예방 또는 치료용 조성물
KR102030123B1 (ko) 2018-05-31 2019-10-08 경희대학교 산학협력단 난청의 예방 또는 치료용 조성물
KR102131044B1 (ko) 2018-05-31 2020-07-08 경희대학교 산학협력단 난청의 예방 또는 치료용 조성물
KR102035845B1 (ko) 2018-05-31 2019-10-23 경희대학교 산학협력단 난청의 예방 또는 치료용 조성물
CN109260152A (zh) * 2018-11-13 2019-01-25 禹州市中医院 一种盐酸洛美沙星滴耳液
CN112022805A (zh) * 2020-10-20 2020-12-04 内蒙古盛唐国际蒙医药研究院有限公司 一种高稳定性复方醋酸氟轻松酊及其制备方法
KR20220091176A (ko) 2020-12-23 2022-06-30 (주)인비보텍 난청의 예방 또는 치료용 조성물
KR20220091177A (ko) 2020-12-23 2022-06-30 (주)인비보텍 난청의 예방 또는 치료용 조성물
US11672798B2 (en) 2021-06-03 2023-06-13 Laboratorios Salvat, S.A. Ciprofloxacin ophthalmic topical composition for treating ocular disease

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1013180A (en) * 1962-10-30 1965-12-15 Ici Ltd Steroid compositions
US3326808A (en) * 1965-08-25 1967-06-20 Pfizer & Co C Antiseptic detergent composition
GB1133800A (en) * 1966-11-10 1968-11-20 Ici Ltd Pharmaceutical compositions
GB1411432A (en) * 1972-01-10 1975-10-22 Medisan Ab Skin treating compositions
AU7776275A (en) 1974-04-11 1976-08-05 Warner Lambert Co Production of base for topical steroids
US4013792A (en) * 1974-04-11 1977-03-22 Warner-Lambert Company Process for the production of base for topical steroids
US3934013A (en) 1975-02-21 1976-01-20 Syntex (U.S.A.) Inc. Pharmaceutical composition
DE3704907A1 (de) 1987-02-17 1988-08-25 Bayer Ag Topisch anwendbare zubereitungen von gyrase-inhibitoren in kombination mit kortikosteroiden
AU4201189A (en) 1988-08-26 1990-03-23 Alcon Laboratories, Inc. Combination of quinolone antibiotics and steroids for topical ophthalmic use
US5897858A (en) * 1994-02-03 1999-04-27 Schering-Plough Healthcare Products, Inc. Nasal spray compositions exhibiting increased retention in the nasal cavity
PT782448E (pt) 1995-06-06 2002-07-31 Bayer Ag Formulacoes oticas antibacterianas nao ototoxicas nao sensibilizantes nao irritantes
ES2106680B1 (es) 1995-08-03 1998-07-01 Vita Invest Sa Composiciones acuosas conteniendo ciprofloxacino y utilizacion y procedimiento correspondientes.
US6274634B1 (en) * 1997-05-14 2001-08-14 Senju Pharmaceutical Co., Ltd. Aqueous suspension preparations with excellent redispersibility
US5997518A (en) * 1998-01-14 1999-12-07 Laibovitz; Robert A. Apparatus and method for delivery of small volumes of liquid
US5990100A (en) * 1998-03-24 1999-11-23 Panda Pharmaceuticals, L.L.C. Composition and method for treatment of psoriasis
JP2002513750A (ja) 1998-05-07 2002-05-14 エラン コーポレーシヨン ピーエルシー 溶媒／助溶剤を含まないマイクロエマルジョン及びエマルジョンプレ濃縮物のドラッグデリバリーシステム
US6241969B1 (en) * 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
TR200200737T2 (tr) 1999-09-24 2002-08-21 Alcon, Inc. Siproflaksasin ve deksametazon içeren lokal süspansiyon formülasyonları
US6235722B1 (en) * 1999-09-24 2001-05-22 Balakrishnan Jayapathy Pharmacological preparation
US20010049366A1 (en) * 2000-02-09 2001-12-06 Alcon Universal Ltd. Topical solution formulations containing an antibiotic and a corticosteroid
US20030195179A1 (en) * 2000-08-25 2003-10-16 Shirou Sawa Aqueous suspension preparations
US20040097592A1 (en) * 2000-09-13 2004-05-20 Kenji Morishima Eye drops
JP2006510657A (ja) * 2002-12-06 2006-03-30 アライバ ファーマシューティカルズ，インコーポレイティド 中耳炎の処置のための方法および組成物
EP1651210A1 (en) * 2003-07-31 2006-05-03 Pharmacia & Upjohn Company LLC Dispersible formulation of an anti-inflammatory agent
DE10347994A1 (de) * 2003-10-15 2005-06-16 Pari GmbH Spezialisten für effektive Inhalation Wässrige Aerosol-Zubereitung
GB0413954D0 (en) * 2004-06-22 2004-07-28 Altunkaya Ali Compositions for topical treatment
US20090111780A1 (en) 2007-10-31 2009-04-30 Everett Laboratories, Inc. Compositions and methods for treatment of ear canal infection and inflammation
WO2010011466A2 (en) * 2008-06-27 2010-01-28 Otonomy, Inc. Controlled-release cns modulating compositions and methods for the treatment of otic disorders
US8318817B2 (en) * 2008-07-21 2012-11-27 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders

Also Published As

Publication number Publication date
JP5744922B2 (ja) 2015-07-08
PL2366408T3 (pl) 2013-01-31
CA2790652A1 (en) 2011-09-09
AR080368A1 (es) 2012-04-04
BR112012021638A2 (pt) 2017-08-08
CA2790652C (en) 2016-11-08
RU2012141641A (ru) 2014-04-10
DK2366408T3 (da) 2012-10-22
EP2366408A1 (en) 2011-09-21
BR112012021638B1 (pt) 2020-10-27
WO2011107436A3 (en) 2011-11-10
KR20130026430A (ko) 2013-03-13
KR101777157B1 (ko) 2017-09-26
AU2011223095B2 (en) 2015-09-17
CN102811741A (zh) 2012-12-05
RU2549465C2 (ru) 2015-04-27
AU2011223095A1 (en) 2012-08-16
US8932610B2 (en) 2015-01-13
JP2013521245A (ja) 2013-06-10
HK1162145A1 (en) 2012-08-24
US20110212932A1 (en) 2011-09-01
WO2011107436A2 (en) 2011-09-09
ES2391721T3 (es) 2012-11-29
CN102811741B (zh) 2015-05-13
MX2012010009A (es) 2012-09-28

Similar Documents

Publication Publication Date Title
EP2366408B1 (en) Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation
EP0782448B1 (en) Non-irritation, non-sensitizing, non-ototoxic otic antibacterial compositions
EP2785328B1 (en) Novel slow-releasing ophthalmic compositions comprising povidone iodine
US20010034339A1 (en) Topical suspension formulations containing ciprofloxacin and dexamethasone
TWI495469B (zh) 含有氟喹諾酮抗生素藥物之經改良藥學組成物
KR20050086937A (ko) 안구 건조의 치료에 있어서 리멕솔론의 용도
US20040126414A1 (en) Methods and compositions for treating and preventing ear infections
CN111821261B (zh) 用于制备无菌眼用水性丙酸氟替卡松a型纳米晶体混悬液的方法
US20230088371A1 (en) Ophthalmic pharmaceutical compositions of roflumilast
WO2019154895A1 (en) Gel formulation for preventing or treating hearing loss
KR102175743B1 (ko) 피나플록사신 현탁 조성물
CN116570558B (zh) 一种伏立康唑眼用纳米缓释组合物及其制备方法和应用
CN109806224B (zh) 一种奥洛他定组合物及其制备方法
CN116847826A (zh) 包含左氧氟沙星和酮咯酸的眼用组合物、其制备方法和用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

AX Request for extension of the european patent

Extension state: AL BA ME RS

17P Request for examination filed

Effective date: 20111011

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/14 20060101ALI20111220BHEP

Ipc: A61K 47/38 20060101ALI20111220BHEP

Ipc: A61K 47/10 20060101AFI20111220BHEP

Ipc: A61K 31/58 20060101ALI20111220BHEP

Ipc: A61K 47/32 20060101ALI20111220BHEP

Ipc: A61K 9/00 20060101ALI20111220BHEP

Ipc: A61K 47/12 20060101ALI20111220BHEP

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

RIN1 Information on inventor provided before grant (corrected)

Inventor name: IZQUIERDO TORRES, FRANCISCA

Inventor name: RUIZ I POL, JAUME

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 566779

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120815

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1162145

Country of ref document: HK

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602010002211

Country of ref document: DE

Effective date: 20120913

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20120718

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2391721

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20121129

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20120718

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 566779

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120718

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

Effective date: 20120718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121118

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121019

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121119

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

26N No opposition filed

Effective date: 20130419

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1162145

Country of ref document: HK

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121018

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010002211

Country of ref document: DE

Effective date: 20130419

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130331

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140331

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130301

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20100301

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120718

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FI

Payment date: 20240325

Year of fee payment: 15

Ref country code: DE

Payment date: 20240327

Year of fee payment: 15

Ref country code: GB

Payment date: 20240327

Year of fee payment: 15

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20240222

Year of fee payment: 15

Ref country code: SE

Payment date: 20240327

Year of fee payment: 15

Ref country code: PL

Payment date: 20240226

Year of fee payment: 15

Ref country code: NO

Payment date: 20240228

Year of fee payment: 15

Ref country code: IT

Payment date: 20240321

Year of fee payment: 15

Ref country code: FR

Payment date: 20240325

Year of fee payment: 15

Ref country code: DK

Payment date: 20240325

Year of fee payment: 15

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240402

Year of fee payment: 15